Up-regulation of matrix metalloproteinase-9 in human myometrium during labour: a cytokine-mediated process in uterine smooth muscle cells

Abstract

The pregnant uterus undergoes dramatic changes of tissue remodelling during the labour and post-partum period. We studied the production of matrix metalloproteinase 9 (MMP-9), as a major contributor of tissue remodelling, in human myometrium at parturition. The regulation of proMMP-9 by interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNF-alpha) was also investigated in human myometrial smooth muscle cells. MMP-9 was present in myometrial smooth muscle cells, interstitial fibroblasts and inflammatory cells. The gelatinolytic activities of proMMP-9 in myometrium increased dramatically during labour. IL-1beta and TNF-alpha induced proMMP-9 in myometrial smooth muscle cells, but these effects did not seem to be mediated by protein kinase C. On the other hand, neither 17beta-oestradiol nor progesterone itself affected proMMP-9 production in myometrial smooth muscle cells. Moreover, progesterone, which is known as a physiological suppressor of MMP-9 in other species, did not decrease the IL-1beta- and TNF-alpha-induced production of proMMP-9. These results suggest that IL-1beta and TNF-alpha are effective up-regulators of proMMP-9 in the tissue remodelling of human myometrium during labour.

Identification of human myometrial target genes of the c-Jun NH2-terminal kinase (JNK) pathway: the role of activating transcription factor 2 (ATF2) and a novel spliced isoform ATF2-small

“…Genes from the tumour necrosis factor receptor superfamily (TNFR) have significant roles in the myometrium due to the importance of TNF in gestation; this is expressed by myometrial stromal cells during pregnancy, although the major source in the myometrium is thought to be macrophages and other leukocytes (Yelavarthi et al 1991, Tabibzadeh et al 1994, Young et al 2002. It stimulates the production of arachadonic acid and prostaglandins (in particular the stimulatory PGF1 ) (Pollard & Mitchell 1996a, b, Hertelendy et al 2002; up-regulates matrix metalloproteinase-9 (MMP-9), which is involved in tissue remodelling of the myometrium during labour (Roh et al 2000); increases adenylyl cyclase (AC) activity in myometrial cells (Gogarten et al 2003); and may prepare the myometrium for labour by regulating the cyclic-ADP-ribose-signalling (cADPR) pathway which controls the development of intracellular Ca 2+ transients (Barata et al 2004).…”

Interaction between Pathogenic Bacteria and Intrauterine Leukocytes Triggers Alternative Molecular Signaling Cascades Leading to Labor in Women

“…Bacteria colonizing the lower genital tract may ascend to the gestational tissues, triggering an inflammatory response mediated primarily by interleukin-1␤ (IL-1␤), tumor necrosis factor alpha (TNF-␣), and IL-6 (14,25,41). These cytokines stimulate the secretion of additional cytokines and other mediators, including uterotonic compounds, such as prostaglandin E 2 (PGE 2 ) (9,27,42) and matrix metalloproteinases (MMPs) (3,33,37), which participate in the weakening of the fetal membranes and their consequent rupture (41,47). However, the interactions between these microorganisms and the fetal membranes that lead to the secretion of these biochemical mediators, and their cellular origins, are poorly understood.…”

RAF1 is increased in labouring myometrium and modulates inflammation-induced pro-labour mediators

“…It induces basal and store-operated calcium entry in myometrial smooth muscle cells (Tribe et al 2003), thus directly enhancing their contractile potential. IL1B can also increase the production of pro-inflammatory cytokines and chemokines; promote the production of prostaglandins via PTGS2, mediators of uterine contractions; and matrix metalloproteinases (MMPs) which activate cervical ripening and foetal membrane rupture, events culminating in successful labour and delivery (Roh et al 2000, Bowen et al 2002, Keelan et al 2003, Lappas & Rice 2004, Christiaens et al 2008, Tattersall, et al 2008. The findings of this study demonstrate that RAF1 is involved in the genesis of pro-inflammatory and RAF1 and labour in myometrium pro-labour mediators induced by IL1B.…”

“…TNF is another pro-inflammatory cytokine that plays a central role in the terminal effector pathways of human labour and deliver. TNF can amplify or initiate the process of parturition by further increasing cytokine production, increasing PTGS2-mediated prostaglandin synthesis and activating MMPs (Roh et al 2000, Bowen et al 2002, Keelan et al 2003, Lappas & Rice 2004, Christiaens et al 2008, Tattersall et al 2008. In addition, TNF can induce preterm labour in animal models (Sadowsky et al 2006).…”

“…In non-gestational tissues, RAF1 has been shown to regulate inflammation via the pro-inflammatory transcription factor NF-kB (Nakano et al 1998, Baumann et al 2000, Roh et al 2000, Keelan et al 2003, Lappas & Rice 2004, Edelblum et al 2008a,b, Lu et al 2010. Thus, to determine whether NF-kB is involved in the RAF1 pathway, the effect of siRAF1 on NF-kB transcriptional activity was determined.…”